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OtherTOXICOLOGY

Liver Toxicity from Norcocaine Nitroxide, an N-Oxidative Metabolite of Cocaine

Florence M. Ndikum-Moffor, Trenton R. Schoeb and Stephen M. Roberts
Journal of Pharmacology and Experimental Therapeutics January 1998, 284 (1) 413-419;
Florence M. Ndikum-Moffor
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Trenton R. Schoeb
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Stephen M. Roberts
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Abstract

The oxidative metabolism of cocaine to norcocaine nitroxide has been postulated to be essential for cocaine hepatotoxicity. The hepatic effects of norcocaine nitroxide have never been evaluated in vivo, however. In this study mice were administered norcocaine nitroxide i.p., and hepatotoxicity was assessed using serum alanine aminotransferase activities and microscopic examination of liver tissue. Hepatotoxicity of norcocaine nitroxide was dose-related; significant injury was detectable at doses of 20 to 30 mg/kg i.p., and severe hepatocellular necrosis was observed at doses of 40 and 50 mg/kg. Elevated serum alanine aminotransferase activities peaked between 12 and 18 hr after norcocaine nitroxide treatment. Electron microscopy revealed the presence of pronounced changes in cell morphology as early as 30 min after the norcocaine nitroxide dose. Pretreatment of mice with phenobarbital had no effect on the magnitude of hepatic injury but shifted the intralobular site of necrosis from the midzonal to the periportal region. Pretreatment with diazinon, an esterase inhibitor, increased norcocaine nitroxide-induced liver damage, whereas each of the P450 inhibitors SKF 525A, cimetidine, troleandomycin, ketaconazole and chloramphenicol significantly diminished norcocaine nitroxide hepatotoxicity. The results indicate that norcocaine nitroxide is hepatotoxic and suggest the involvement of P450 enzymes.

Footnotes

  • Send reprint requests to: Dr. Stephen M. Roberts, Center for Environmental & Human Toxicology, University of Florida, Box 110885, Gainesville, Florida 32611.

  • ↵1 This research was supported by a grant from the National Institute on Drug Abuse (DA 06601).

  • Abbreviations:
    ALT
    alanine aminotransferase
    ESR
    electron spin resonance
    TEM
    transmission electron microscopy
    TLC
    thin-layer chromatography
    • Received April 9, 1997.
    • Accepted September 22, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 1
1 Jan 1998
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OtherTOXICOLOGY

Liver Toxicity from Norcocaine Nitroxide, an N-Oxidative Metabolite of Cocaine

Florence M. Ndikum-Moffor, Trenton R. Schoeb and Stephen M. Roberts
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 413-419;

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OtherTOXICOLOGY

Liver Toxicity from Norcocaine Nitroxide, an N-Oxidative Metabolite of Cocaine

Florence M. Ndikum-Moffor, Trenton R. Schoeb and Stephen M. Roberts
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 413-419;
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